Research: In recent years, new sequencing technologies, combined with the advent of large consortia, have enabled broad public availability of massive amounts of genomic data. These resources provide great opportunities for enhancing our understanding of the human genome and of the role of epigenetic mechanisms in disease etiology. We propose to integrate genomics data to uncover causal variants in complex traits and diseases, and to highlight their specific influence on relevant cell types, transcription factors and regulated genes. The contribution of this proposal is a systems-level analysis of Genome Wide Association Studies (GWAS) that integrate genetic, epigenetic and gene expression data, to uncover disease-causal non-coding variants by quantifying their effect on transcription factor binding sites for different chromatin states. The innovation of the proposed research consists in the use of novel computational strategies based on statistical and information theoretic approaches, and a web platform that will make the results and tools derived from the proposed research, broadly available and accessible to the scientific community. The experimental strategy will offer an important and general framework for scrutinizing epigenetic and genetic variations, and for generating insights and testable hypotheses to reveal causal genetic variants that underlie complex traits and diseases. We expect that our findings will promote future development of personalized therapeutic approaches. Candidate Career Goals: Dr. Pinello's career goal is to become an independent investigator to systematically study the sources of variation that affect gene regulation in complex traits and diseases by linking genetic and epigenetic variation. The K99/R00 award will give him the protected time needed to obtain the additional knowledge and expertise necessary to achieve this goal. The proposed research is complemented by a structured plan that spells out specific training activities and career development components. Dr. Pinello will supplement his hands-on training with formal coursework and specific mentored research exploration focused in three main areas: Medical Genetics, Functional Genomics and Experimental Techniques. To oversee his training and proposed research, Dr. Pinello has assembled a mentoring team with complementary skills. By combining expertise in epigenetic and gene regulation with population and medical genetics, at the end of the award period Dr. Pinello will have developed a broad set of skills and a research focus that is distinct from his current lab. He will thus be a fully qualified independent investigator. Environment: The Department of Biostatistics and Computational Biology at the Dana-Farber Cancer Institute/Harvard School of Public Health has a distinguished record of training successful scientists, and is an excellent environment for conducting research. The Dana-Farber Cancer Institute, Harvard Medical School, the Harvard School of Public Health, the Broad Institute of MIT and Harvard, and the hospitals and institutions of the Partners Consortium provide a rich and vibrant academic environment in Boston and Cambridge.